Compositions useful as inhibitors of JAK and other protein kinases

ABSTRACT

The present invention provides a compound of formula I: 
                         
or a pharmaceutically acceptable salt thereof. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 60/423,579, filed Nov. 4, 2002, entitled“Compositions Useful as Inhibitors of Jak and Other Protein Kinases, theentire contents of which is hereby incorporated by reference.

TECHNICAL FIELD OF INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250–300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576–596;Knighton et al., Science 1991, 253, 407–414; Hiles et al., Cell 1992,70, 419–429; Kunz et al., Cell 1993, 73, 585–596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352–2361).

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events. These diseases include autoimmunediseases, inflammatory diseases, bone diseases, metabolic diseases,neurological and neurodegenerative diseases, cancer, cardiovasculardiseases, allergies and asthma, Alzheimer's disease and hormone-relateddiseases. Accordingly, there has been a substantial effort in medicinalchemistry to find protein kinase inhibitors that are effective astherapeutic agents.

The Janus kinases (JAK) are a family of tyrosine kinases consisting ofJAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokinesignaling. The down-stream substrates of the JAK family of kinasesinclude the signal transducer and activator of transcription (STAT)proteins. JAK/STAT signaling has been implicated in the mediation ofmany abnormal immune responses such as allergies, asthma, autoimmunediseases such as transplant rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis as well as in solid andhematologic malignancies such as leukemias and lymphomas. Thepharmaceutical intervention in the JAK/STAT pathway has been reviewed[Frank Mol. Med. 5, 432–456 (1999) & Seidel, et al, Oncogene 19,2645–2656 (2000)].

JAK1, JAK2, and TYK2 are ubiquitously expressed, while JAK3 ispredominantly expressed in hematopoietic cells. JAK3 binds exclusivelyto the common cytokine receptor gamma chain (γ_(c)) and is activated byIL-2, IL-4, IL-7, IL-9, and IL-15. The proliferation and survival ofmurine mast cells induced by IL-4 and IL-9 have, in fact, been shown tobe dependent on JAK3- and γ_(c)-signaling [Suzuki et al, Blood 96,2172–2180 (2000)].

Cross-linking of the high-affinity immunoglobulin (Ig) E receptors ofsensitized mast cells leads to a release of proinflammatory mediators,including a number of vasoactive cytokines resulting in acute allergic,or immediate (type I) hypersensitivity reactions [Gordon et al, Nature346, 274–276 (1990) & Galli, N. Engl. J. Med., 328, 257–265 (1993)]. Acrucial role for JAK3 in IgE receptor-mediated mast cell responses invitro and in vivo has been established [Malaviya, et al, Biochem.Biophys. Res. Commun. 257, 807–813 (1999)]. In addition, the preventionof type I hypersensitivity reactions, including anaphylaxis, mediated bymast cell-activation through inhibition of JAK3 has also been reported[Malaviya et al, J. Biol. Chem. 274,27028–27038 (1999)]. Targeting mastcells with JAK3 inhibitors modulated mast cell degranulation in vitroand prevented IgE receptor/antigen-mediated anaphylactic reactions invivo.

A recent study described the successful targeting of JAK3 for immunesuppression and allograft acceptance. The study demonstrated adose-dependent survival of Buffalo heart allograft in Wistar Furthrecipients upon administration of inhibitors of JAK3 indicating thepossibility of regulating unwanted immune responses in graft versus hostdisease [Kirken, Transpl. Proc. 33, 3268–3270 (2001)].

IL-4-mediated STAT-phosphorylation has been implicated as the mechanisminvolved in early and late stages of rheumatoid arthritis (RA).Up-regulation of proinflammatory cytokines in RA synovium and synovialfluid is a characteristic of the disease. It has been demostrated thatIL-4-mediated activation of IL-4/STAT pathway is mediated through theJanus Kinases (JAK 1 & 3) and that IL-4-associated JAK kinases areexpressed in the RA synovium [Muller-Ladner, et al, J. Immunol. 164,3894–3901 (2000)].

Familial amyotrophic lateral sclerosis (FALS) is a fatalneurodegenerative disorder affecting about 10% of ALS patients. Thesurvival rates of FALS mice were increased upon treatment with a JAK3specific inhibitor. This suggested that JAK3 plays a role in FALS[Trieu, et al, Biochem. Biophys. Res. Commun. 267, 22–25 (2000)].

Signal transducer and activator of transcription (STAT) proteins areactivated by, among others, the JAK family kinases. Results form arecent study suggested the possibility of intervention in the JAK/STATsignaling pathway by targeting JAK family kinases with specificinhibitors for the treatment of leukemia [Sudbeck, et al, Clin. CancerRes. 5, 1569–1582 (1999)]. JAK3 specific compounds were shown to inhibitthe clonogenic growth of JAK3-expressing cell lines DAUDI, RAMOS,LC1;19, NALM-6, MOLT-3 and HL-60.

In animal models, TEL/JAK2 fusion proteins have inducedmyeloproliferative disorders and in hematopoietic cell lines,introduction of TEL/JAK2 resulted in activation of STAT1, STAT3, STAT5,and cytokine-independent growth [Schwaller, et al, EMBO J. 17, 5321–5333(1998)].

Inhibition of JAK 3 and TYK 2 abrogated tyrosine phosphorylation ofSTAT3, and inhibited cell growth of mycosis fungoides, a form ofcutaneous T cell lymphoma. These results implicated JAK family kinasesin the constitutively activated JAK/STAT pathway that is present inmycosis fungoides [Nielsen, et al, Proc. Nat. Acad. Sci. U.S.A. 94,6764–6769 (1997)]. Similarly, STAT3, STAT5, JAK1 and JAK2 weredemonstrated to be constitutively activated in mouse T cell lymphomacharacterized initially by LCK over-expression, thus further implicatingthe JAK/STAT pathway in abnormal cell growth [Yu, et al, J. Immunol.159, 5206–5210 (1997)]. In addition, IL-6-mediated STAT3 activation wasblocked by an inhibitor of JAK, leading to sensitization of myelomacells to apoptosis [Catlett-Falcone, et al, Immunity 10 ,105–115(1999)].

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinasesconsisting of a β-sheet rich amino-terminal lobe and a largercarboxy-terminal lobe which is largely α-helical. The CDKs display the11 subdomains shared by all protein kinases and range in molecular massfrom 33 to 44 kD. This family of kinases, which includes CDK1, CKD2,CDK4, and CDK6, requires phosphorylation at the residue corresponding toCDK2 Thr160 in order to be fully active [Meijer, L., Drug ResistanceUpdates, 3, 83–88 (2000)].

Each CDK complex is formed from a regulatory cyclin subunit (e.g.,cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit(e.g., CDK1, CDK2, CDK4, CDK5, and CDK6). Each different kinase/cyclinpair functions to regulate the different and specific phases of the cellcycle known as the G1, S, G2, and M phases [Nigg, E., Nature Reviews, 2,21–32 (2001); Flatt, P., Pietenpol, J., Drug Metabolism Reviews, 32,283–305 (2000)].

The CDKs have been implicated in cell proliferation disorders,particularly in cancer. Cell proliferation is a result of the direct orindirect deregulation of the cell division cycle and the CDKs play acritical role in the regulation of the various phases of this cycle. Forexample, the over-expression of cyclin D1 is commonly associated withnumerous human cancers including breast, colon, hepatocellularcarcinomas and gliomas [Flatt, P., Pietenpol, J., Drug MetabolismReviews, 32, 283–305 (2000)]. The CDK2/cyclin E complex plays a key rolein the progression from the early G₁ to S phases of the cell cycle andthe overexpression of cyclin E has been associated with various solidtumors. Therefore, inhibitors of cyclins D1, E, or their associated CDKsare useful targets for cancer therapy [Kaubisch, A., Schwartz, G., TheCancer Journal, 6, 192–212 (2000)].

CDKs, especially CDK2, also play a role in apoptosis and T-celldevelopment. CDK2 has been identified as a key regulator of thymocyteapoptosis [Williams, O., et al, European Journal of Immunology, 709–713(2000)]. Stimulation of CDK2 kinase activity is associated with theprogression of apoptosis in thymocytes, in response to specific stimuli.Inhibition of CDK2 kinase activity blocks this apoptosis resulting inthe protection of thymocytes.

In addition to regulating the cell cycle and apoptosis, the CDKs aredirectly involved in the process of transcription. Numerous virusesrequire CDKs for their replication process. Examples where CDKinhibitors restrain viral replication include human cytomegakovirus,herpes virus, and varicella-zoster virus [Meijer, L., Drug ResistanceUpdates, 3, 83–88 (2000)].

Inhibition of CDK is also useful for the treatment of neurodegenerativedisorders such as Alzheimer's disease. The appearance of Paired HelicalFilaments (PHF), associated with Alzheimer's disease, is caused by thehyperphosphorylation of Tau protein by CDK5/p25 [Meijer, L., DrugResistance Updates, 3, 83–88 (2000)].

JNK is a member of the mitogen-activated protein (MAP) kinase family.MAP kinases (MAPKs) are activated by a variety of signals includinggrowth factors, cytokines, UV radiation, and stress-inducing agents.MAPKs are serine/threonine kinases and their activation occur by dualphosphorylation of threonine and tyrosine at the Thr-X-Tyr segment inthe activation loop. MAPKs phosphorylate various substrates includingtranscription factors, which in turn regulate the expression of specificsets of genes and thus mediate a specific response to the stimulus.

Three distinct genes, JNK1, JNK2, JNK3 have been identified for thiskinase family and at least ten different splicing isoforms of JNKs existin mammalian cells [Gupta et al., EMBO J., 15, 2760–70 (1996)]. Membersof the JNK family are activated by proinflammatory cytokines, such astumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β), as well asby environmental stress, including anisomycin, UV irradiation, hypoxia,and osmotic shock [Minden et al., Biochemica et Biophysica Acta, 1333,F85–F104 (1997)].

The down-stream substrates of JNKs include transcription factors c-Jun,ATF-2, Elk1, p53 and a cell death domain protein (DENN) [Zhang et al.Proc. Natl. Acad. Sci. USA, 95, 2586–91 (1998)]. Each JNK isoform bindsto these substrates with different affinities, suggesting a regulationof signaling pathways by substrate specificity of different JNKs in vivo(Gupta et al., supra).

JNKs, along with other MAPKs, have been implicated in having a role inmediating cellular response to cancer, thrombin-induced plateletaggregation, immunodeficiency disorders, autoimmune diseases, celldeath, allergies, osteoporosis and heart disease. The therapeutictargets related to activation of the JNK pathway include chronicmyelogenous leukemia (CML), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer and neurodegenerative diseases.

Several reports have detailed the importance of JNK activationassociated with liver disease or episodes of hepatic ischemia [Nat.Genet. 21, 326–9 (1999); FEBS Lett. 420, 201–4 (1997); J. Clin. Invest.102, 1942–50 (1998); Hepatology 28, 1022–30 (1998)]. Therefore,inhibitors of JNK may be useful to treat various hepatic disorders.

A role for JNK in cardiovascular disease such as myocardial infarctionor congestive heart failure has also been reported as it has been shownJNK mediates hypertrophic responses to various forms of cardiac stress[Circ. Res. 83, 167–78 (1998); Circulation 97, 1731–7 (1998); J. Biol.Chem. 272, 28050–6 (1997); Circ. Res. 79, 162–73 (1996); Circ. Res. 78,947–53 (1996); J. Clin. Invest. 97, 508–14 (1996)].

It has been demonstrated that the JNK cascade also plays a role inT-cell activation, including activation of the IL-2 promoter. Thus,inhibitors of JNK may have therapeutic value in altering pathologicimmune responses [J. Immunol. 162, 3176–87 (1999); Eur. J. Immunol. 28,3867–77 (1998); J. Exp. Med. 186, 941–53 (1997); Eur. J. Immunol. 26,989–94 (1996)].

A role for JNK activation in various cancers has also been established,suggesting the potential use of JNK inhibitors in cancer. For example,constitutively activated JNK is associated with HTLV-1 mediatedtumorigenesis [Oncogene 13, 135–42 (1996)]. JNK may play a role inKaposi's sarcoma (KS) because it is thought that the proliferativeeffects of bFGF and OSM on KS cells are mediated by their activation ofthe JNK signaling pathway [J. Clin. Invest. 99, 1798–804 (1997)]. Otherproliferative effects of other cytokines implicated in KS proliferation,such as vascular endothelial growth factor (VEGF), IL-6 and TNFα, mayalso be mediated by JNK. In addition, regulation of the c-jun gene inp210 BCR-ABL transformed cells corresponds with activity of JNK,suggesting a role for JNK inhibitors in the treatment for chronicmyelogenous leukemia (CML) [Blood 92, 2450–60 (1998)].

JNK1 and JNK2 are widely expressed in a variety of tissues. In contrast,JNK3, is selectively expressed in the brain and to a lesser extent inthe heart and testis [Gupta et al., supra; Mohit et al., Neuron 14,67–78 (1995); Martin et al., Brain Res. Mol. Brain Res. 35, 47–57(1996)]. JNK3 has been linked to neuronal apoptosis induced by kainicacid, indicating a role of JNK in the pathogenesis of glutamateneurotoxicity. In the adult human brain, JNK3 expression is localized toa subpopulation of pyramidal neurons in the CA1, CA4 and subiculumregions of the hippocampus and layers 3 and 5 of the neocortex [Mohit etal., supra]. The CA1 neurons of patients with acute hypoxia showedstrong nuclear JNK3-immunoreactivity compared to minimal, diffusecytoplasmic staining of the hippocampal neurons from brain tissues ofnormal patients [Zhang et al., supra]. Thus, JNK3 appears to be involvedinvolved in hypoxic and ischemic damage of CA1 neurons in thehippocampus.

In addition, JNK3 co-localizes immunochemically with neurons vulnerablein Alzheimer's disease [Mohit et al., supra]. Disruption of the JNK3gene caused resistance of mice to the excitotoxic glutamate receptoragonist kainic acid, including the effects on seizure activity, AP-1transcriptional activity and apoptosis of hippocampal neurons,indicating that the JNK3 signaling pathway is a critical component inthe pathogenesis of glutamate neurotoxicity (Yang et al., Nature, 389,,865–870 (1997)].

Based on these findings, JNK signalling, especially that of JNK3, hasbeen implicated in the areas of apoptosis-driven neurodegenerativediseases such as Alzheimer's Disease, Parkinson's Disease, ALS(Amyotrophic Lateral Sclerosis), epilepsy and seizures, Huntington'sDisease, traumatic brain injuries, as well as ischemic and hemorrhagingstroke.

ZAP-70 is essential for T cell receptor signalling. Expression of thistyrosine kinase is restricted to T-cells and natural killer cells. Theimportance of ZAP-70 in T-cell function has been demonstrated in humanpatients, human T-cell lines and mice. Human patients suffering from arare form of severe combined deficiency syndrome (SCID) possesshomozygous mutations in ZAP-70 (reviewed in Elder J. of pedriatrichematology/oncology 19(6) 546–550 1997). These patients have profoundimmunodeficiency, lack CD8+ T cells and have CD4+ T cells that areunresponsive to T cell receptor (TCR)-mediated stimulation. FollowingTCR activation these CD4+ cells show severe defects in Ca2+mobilization, tyrosine phosphorylation of down-stream substrates,proliferation and IL-2 production 70 (reviewed in Elder Pedriatricresearch 39, 743–748). Human Jurkat cells lacking ZAP-70 also provideimportant insights into the critical role of ZAP-70 in T cell receptorsignalling. A Jurkat clone (p116) with no detectable ZAP-70 protein wasshown to have defects in T cell receptor signalling which could becorrected by re-introduction of wt ZAP-70 (Williams et al Molecular andCellular Biology 18 (3), 1388–1399 1998). Studies of mice lacking ZAP-70also demonstrate a requirement of ZAP-70 in T-cell receptor signalling.Zap-70-deficient mice have profound defects in T cell development and Tcell receptor signalling in thymocytes is impaired (Negishi et al,Nature 376, 435–438 1995).

The importance of the kinase domain in ZAP-70 function is demonstratedby studies of human patients and mice expressing identical mutations inthe DLAARN motif within the kinase domain of ZAP-70. Inactivation ofkinase activity by this mutation results in defective T cell receptorsignalling (Elder et al J. Immunology 656–661 2001). Catalyticallyinactive ZAP-70 (Lys369Arg) was also defective in restoring T cellreceptor signalling in a ZAP-70 deficient Jurkat cell clone (p116)(Williams et al Molecular and Cellular Biology 18 (3), 1388–1399 1998).

Accordingly, there is a great need to develop inhibitors of JAK, INK,CDK, and ZAP-70 protein kinases that are useful in treating variousdiseases or conditions associated with JAK, INK, CDK, and ZAP-70activation, particularly given the inadequate treatments currentlyavailable for the majority of these disorders.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of JAK, INK, ZAP-70, and CDK protein kinases. In certainembodiments, these compounds are effective as inhibitors of JAK, JNK,ZAP-70, and CDK protein kinases. These compounds have the generalformula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein W¹ is        nitrogen or CH, W² is nitrogen or C—(U)_(p)R^(U), W³ is nitrogen        or C—(V)_(q)R^(V), and R¹, R², R³, and R⁴ are as described        below.

These compounds and pharmaceutical compositions thereof are useful fortreating or preventing a variety of disorders, such as heart disease,diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatorydiseases, allergic diseases, autoimmune diseases, destructive bonedisorders such as osteoporosis, proliferative disorders, infectiousdiseases, immunologically-mediated diseases, and viral diseases. Thecompositions are also useful in methods for preventing cell death andhyperplasia and therefore may be used to treat or preventreperfusion/ischemia in stroke, heart attacks, and organ hypoxia. Thecompositions are also useful in methods for preventing thrombin-inducedplatelet aggregation. The compositions are especially useful fordisorders such as chronic myelogenous leukemia (CML), rheumatoidarthritis, asthma, osteoarthritis, ischemia, cancer, liver diseaseincluding hepatic ischemia, heart disease such as myocardial infarctionand congestive heart failure, pathologic immune conditions involving Tcell activation, and neurodegenerative disorders.

The compounds provided by this invention are also useful for the studyof kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases, andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Compounds of the Invention

The present invention relates to a compound of formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:

-   W¹ is nitrogen or CH, W² is nitrogen or C—(U)_(p)R^(U), and W³ is    nitrogen or C—(V)_(q)R^(V);

-   p and q are each independently 0 or 1;

-   R^(U) and R^(V) are each independently R or Ar¹;

-   U and V are each independently a bond or a C₁₋₆ alkylidene chain,    wherein up to two methylene units of the chain are optionally and    independently replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO,    NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR;

-   each occurrence of R is independently hydrogen or an optionally    substituted C₁–C₄ aliphatic, or two R bound to the same nitrogen    atom are optionally taken together with the nitrogen atom to form a    3–7 membered saturated, partially unsaturated, or fully unsaturated    ring having 0–2 additional heteroatoms independently selected from    nitrogen, oxygen, or sulfur;

-   Ar¹ is a 5–7 membered saturated, partially unsaturated, or fully    unsaturated monocyclic ring having 0–3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or an 8–12 membered    saturated, partially unsaturated, or fully unsaturated bicyclic ring    system having 0–5 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; wherein Ar¹ is optionally substituted with m    independent occurrences of Z—R⁵; wherein m is 0–5, Z is a bond or is    a C₁–C₆ alkylidene chain wherein up to two methylene units of Z are    optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO,    NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR;    and each occurrence of R⁵ is independently hydrogen, an optionally    substituted aliphatic, heteroaliphatic, aryl or heteroaryl group,    halogen, NO₂, CN, OR, SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, COR,    CO₂R, OCOR, CON(R)₂, OCON(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R,    NRSO₂N(R)₂, COCOR, or COCH₂COR;

-   R¹ and R² taken together and fused to ring B form a cyclic moiety    selected from one of the following:

-   wherein each occurrence of R^(X) is independently hydrogen, QR, or    Q_(n)Ar¹; n is zero or one; and Q is an optionally substituted C₁₋₄    alkylidene chain wherein one methylene unit of Q is optionally    replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂,    NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR;-   R³ is halogen, QR, Q_(n)CN, Q_(n)NO₂, or Q_(n)Ar¹; and-   R⁴ is Ar¹, or T—Ar¹;    -   wherein T is a C₁₋₂ alkylidene chain wherein one methylene unit        of T is optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR,        NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O,        S, or NR.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1–20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1–10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1–8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1–6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1–4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃–C₈ hydrocarbon or bicyclic C₈–C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3–7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup are generally selected from halogen; —R^(o); —OR^(o); —SR^(o);phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionallysubstituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted withR^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂;—C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o);—C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂;—(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o);—O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionallysubstituted with R^(o); or —CH═CH(Ph), optionally substituted withR^(o); wherein each independent occurrence of R^(o) is selected fromhydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5–6membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph),or, notwithstanding the definition above, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, to form anoptionally substituted 3–12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0–4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Optional substituents on the aliphatic group of R^(o) are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoingC₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the saturated carbon of an aliphatic or heteroaliphaticgroup, or of a non-aromatic heterocyclic ring are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

Unless otherwise defined above and herein, optional substituents on thenitrogen of a non-aromatic heterocyclic ring are generally selected from—R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺,—SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ ishydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5–6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R⁺, on the same substituent ordifferent substituents, taken together with the atom(s) to which each R⁺group is bound, form an optionally substituted 3–12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0–4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,—CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic),wherein each of the foregoing C₁₋₄ aliphatic groups of R⁺ isunsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which they are bound to form anoptionally substituted 3–12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0–4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein) thatare bound to the same atom and are taken together with that atom to forma ring, for example, N(R^(o))₂, where both occurrences of R^(o) aretaken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

3. Description of Exemplary Compounds

In certain embodiments, compounds of Formula I above include thosecompounds where R¹ and R² taken together represent the heterocycle idepicted above.

In certain embodiments, exemplary substituents, R^(X), for the nitrogenatom of heterocycle i are selected from hydrogen and optionallysubstituted C₁₋₆aliphatic. In other embodiments, R^(X) is hydrogen,methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₆alkyl substituted with N(R)₂, or C₁₋₆alkyl substitutedwith Ar¹. In yet other embodiments, R^(X) is hydrogen, methyl, orC₁₋₂alkyl substituted with a group selected from optionally substitutedphenyl, pyridyl, morpholino, piperidinyl, or piperazinyl.

In certain other embodiments, exemplary compounds of Formula I aboveinclude those compounds where R³ is hydrogen, halogen, QR or QAr¹,wherein Q is a C₁₋₃ alkylidene chain wherein one methylene unit of Q isoptionally replaced by —O—, —S—, —NHCO—, or —NR—, and Ar¹ is anoptionally substituted 5–6 membered saturated, partially unsaturated, orfully unsaturated ring having 0–2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In other embodiments R³ is hydrogen,OH, OCH₃, OCH₂CH₃, NHCOMe, NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,O(CH₂)₂morpholin-4-yl, O(CH₂)₂NH₂, O(CH₂)₂NH(C₁₋₄ aliphatic),O(CH₂)₂N(C₁₋₄ aliphatic)₂, Br, Cl, or F. In certain other embodiments,R³ is hydrogen.

In still other embodiments, R⁴ is a 6-membered saturated, partiallyunsaturated, or aryl ring having 0–3 nitrogen atoms, a 9–10 memberedbicyclic aryl ring having 0–2 nitrogens, or a 5 membered heteroaryl ringhaving 2–3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein each ring is optionally substituted. In otherembodiments R⁴ is an optionally substituted rings selected from phenyl,cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, thiazolyl,thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl, or benzimidazolyl. Inyet other embodiments, R⁴ is an optionally substituted phenyl group.

Exemplary substituents on R⁴ are independently selected from Z—R⁵,wherein each occurrence of Z is independently a bond or a C₁₋₆alkylidene chain wherein one methylene unit of Z is optionally replacedby —O—, —S—, —SO₂—, or —NH—; and each occurrence of R⁵ is independentlyhydrogen, C₁₋₆ aliphatic, halogen, NO₂, OR, N(R)₂, or optionallysubstituted phenyl, pyridyl, or pyrimidinyl. In other embodiments eachoccurrence of ZR⁵ is independently Cl, F, Br, methyl, ethyl, t-butyl,isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF₃, NH₂, phenyl, benzyl,benzyloxy, OH, methylene dioxy, SO₂NH₂, CONH₂, CO₂Me, phenoxy,O-pyridinyl, SO₂phenyl, nitrophenoxy, aminophenoxy,S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl,aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl,CF₃-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy,chlorophenoxy, ethoxyphenoxy, or fluorophenoxy.

In exemplary embodiments, m is 0, 1, or 2 and R⁴ is substituted with 0,1 or 2 occurrences of ZR⁵.

In yet other embodiments, W¹ is nitrogen or CH, W² is nitrogen orC—(U)_(p)R^(U), and W³ is nitrogen or C—(V)_(q)R^(V). In still otherembodiments, W¹ is nitrogen or CH, W² is C—(U)_(p)R^(U), and W³ isC—(V)_(q)R^(V). In yet other embodiments, W¹ is nitrogen or CH and W²and W³ are each CH.

Exemplary (U)_(p)R^(U) and (V)_(q)R^(V) groups of formula I, and classesand subclasses thereof as described herein, are each independentlyhydrogen, halogen, NO₂, CN, OR, SR or N(R)₂, or C₁₋₄ aliphaticoptionally substituted with oxo, OR, SR, N(R)₂, halogen, NO₂ or CN. Inother embodiments (U)_(p)R^(U) and (V)_(q)R^(V) groups are eachindependently hydrogen, Me, OH, OMe or N(R)₂. In still otherembodiments, (U)_(p)R^(U) and (V)_(q)R^(V) are each hydrogen.

In certain exemplary embodiments, for compounds of Formula I describeddirectly above, W is N or CH and have the structures of Formulas Ia andIb below:

-   -   or a pharmaceutically acceptable salt thereof, wherein R¹, R²,        R³, and R⁴ are as defined generally above and in classes and        subclasses described herein.

As described generally above, certain exemplary embodiments also relateto those compounds where R⁴ is an optionally substituted phenyl groupand the compounds have the general structures of formulas Ia and IIbdepicted generally below:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0–5,        and R¹, R², R³, Z and R₅ are as defined generally above and in        classes and subclasses described herein.

In certain other exemplary embodiments, R³ is hydrogen, and thecompounds have the general structures of formulas IIIa and IIIb:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0–5,        and R¹, R², R³, Z and R₅ are as defined generally above and in        classes and subclasses described herein.

In yet other exemplary embodiments, R³ is hydrogen, and R¹ and R² takentogether and fused with ring B represent the heterocycle i and thecompounds have the general structures of formulas IVa and IVb:

-   -   or a pharmaceutically acceptable salt thereof, wherein m is 0–5,        and R¹, R², R³, Z and R₅ are as defined generally above and in        classes and subclasses described herein.

Certain subclasses of the foregoing compounds are described in moredetail below. It will be appreciated that, for each of the compoundsgenerally described above (formula I) and classes thereof, (e.g.,formulas IIa, IIb, IIIa, IIIb, IVa and IVb), any combination of thesubsets set forth below may be utilized for each variable to describeexemplary subclasses of the invention. In particular, certain preferredsubsets include, but are not limited to the following compounds where:

-   -   i) R¹ and R² taken together represent the heterocycle i depicted        above; where R^(X) is defined according to one of the following        groups:        -   a. hydrogen or optionally substituted C₁₋₆aliphatic;        -   b. hydrogen, methyl, ethyl, propyl, n-butyl, tert-butyl,            pentyl, cyclopentyl, hexyl, cyclohexyl, C₁₋₆alkyl            substituted with N(R)₂, or C₁₋₆alkyl substituted with Ar¹;            or        -   c. hydrogen, methyl, or C₁₋₂alkyl substituted with a group            selected from optionally substituted phenyl, pyridyl,            morpholino, piperidinyl, or piperazinyl.    -   ii) R³ is defined according to one of the following groups:        -   a. hydrogen, halogen, QR or QAr¹, wherein Q is a C₁₋₃            alkylidene chain wherein one methylene unit of Q is            optionally replaced by —O—, —S—, —NHCO—, or —NR—, and Ar¹ is            an optionally substituted 5–6 membered saturated, partially            unsaturated, or fully unsaturated ring having 0–2            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;        -   b. hydrogen, OH, OCH₃, OCH₂CH₃, NHCOMe, NH₂, NH(C₁₋₄            aliphatic), N(C₁₋₄ aliphatic)₂, O(CH₂)₂morpholin-4-yl,            O(CH₂)₂NH₂, O(CH₂)₂NH(C₁₋₄ aliphatic), O(CH₂)₂N(C₁₋₄            aliphatic)₂, bromo, chloro, or fluoro; or        -   c. hydrogen;    -   iii) R⁴ is defined according to one of the following groups:        -   a. a 6-membered saturated, partially unsaturated, or aryl            ring having 0–3 nitrogens, a 9–10 membered bicyclic aryl            ring having 0–2 nitrogens, or a 5 membered heteroaryl ring            having 2–3 heteroatoms independently selected from nitrogen,            oxygen, or sulfur, wherein each ring is optionally            substituted;        -   b. an optionally substituted ring selected from phenyl,            cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,            thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl,            or benzimidazolyl; or        -   c. an optionally substituted phenyl group;    -   iv) W¹, W² and W³ are defined according to one of the following        groups:        -   a. W¹ is nitrogen or CH, W² is nitrogen or C—(U)_(p)R^(U),            and W³ is nitrogen or C—(V)_(q)R^(V);        -   b. W¹ is nitrogen or CH, W² is C—(U)_(p)R^(U), and W³ is            C—(V)_(q)R^(V); or        -   c. W¹ is nitrogen or CH and W² and W³ are each CH; and    -   v) (U)_(p)R^(U) and (V)_(q)R^(V) groups are defined according to        one of the following groups:        -   a. hydrogen, halogen, NO₂, CN, OR, SR or N(R)₂, or C₁₋₄            aliphatic optionally substituted with oxo, OR, SR, N(R)₂,            halogen, NO₂ or CN;        -   b. hydrogen, Me, OH, OMe or N(R)₂; or        -   c. both (U)_(p)R^(U) and (V)_(q)R^(V) are hydrogen.

It will be appreciated that for the subsets described directly above, incertain exemplary embodiments, each occurrence of R⁴ is independentlyselected from Z—R⁵, wherein each occurrence of Z is independently a bondor a C₁₋₆ alkylidene chain wherein one methylene unit of Z is optionallyreplaced by —O—, —S—, —SO₂—, or —NH—; and each occurrence of R⁵ isindependently hydrogen, C₁₋₆ aliphatic, halogen, NO₂, OR, N(R)₂, oroptionally substituted phenyl, pyridyl, and pyrimidinyl. In otherembodiments, each occurrence of ZR⁵ is independently Cl, F, Br, methyl,ethyl, t-butyl, isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF₃, NH₂,phenyl, benzyl, benzyloxy, OH, methylene dioxy, SO₂NH₂, CONH₂, CO₂Me,phenoxy, O-pyridinyl, SO₂phenyl, nitrophenoxy, aminophenoxy,S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl,aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl,CF₃-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy,chlorophenoxy, ethoxyphenoxy, and fluorophenoxy.

In certain other embodiments, m is 0, 1, or 2 and R⁴ is substituted with0, 1 or 2 occurrences of ZR⁵.

In yet other embodiments, compounds have the formula IVa, where R^(X) ishydrogen or optionally substituted C₁₋₆aliphatic; m is 0, 1 or 2; andZR⁵ is Cl, F, Br, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro,CN, OMe, OEt, CF₃, NH₂, phenyl, benzyl, benzyloxy, OH, methylene dioxy,SO₂NH₂, CONH₂, CO₂Me, phenoxy, O-pyridinyl, SO₂phenyl, nitrophenoxy,aminophenoxy, S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl,pyridinyl, amninophenyl, phenol, chloro-fluoro-phenyl,dimethylaminophenyl, CF₃-phenyl, dimethylphenyl, chlorophenyl,fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, orfluorophenoxy.

Representative examples of compounds of Formula IVa are set forth belowin Table 1.

TABLE 1 Examples of Compounds of Formula IVa:

Representative examples of compounds of Formula IVb are set forth belowin Table 2.

TABLE 2 Examples of Compounds of Formula IVb:

4. General Synthetic Methodology

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated in Scheme I below, and the preparative examples that follow.

As depicted above, eneaminones (3) (N-substituted) can be preparedaccording to procedure D or according to procedures E, F and G (ormodified versions thereof), as described in more detail in theexperimentals herein. Subsequent reaction of eneaminones (3) with asuitable guanidine (6) (the synthesis of which is generally describedherein using procedures A and B) yields a desired phenylaminopyrimidine(4). It will be appreciated that additional ring B systems can beprepared according to the general methods described above and methodsknown in the art using the appropriate starting materials in place ofthe benzoxazin depicted above.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of protein kinases, and thus the present compounds are usefulfor the treatment of diseases, disorders, and conditions including, butnot limited to a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, psychotic disorders, an autoimmune disorder,a condition associated with organ transplant, an inflammatory disorder,an immunologically mediated disorder, a viral disease, or a bonedisorder. In preferred embodiments, the compounds are useful for thetreatment of allergy, asthma, diabetes, Alzheimer's disease,Huntington's disease, Parkinson's disease, AIDS-associated dementia,amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiplesclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia (e.g., stroke), baldness, cancer, hepatomegaly,cardiovascular disease including cardiomegaly, cystic fibrosis, viraldisease, autoimmune diseases, atherosclerosis, restenosis, psoriasis,inflammation, hypertension, angina pectoris, cerebrovascularcontraction, peripheral circulation disorder, premature birth,arteriosclerosis, vasospasm (cerebral vasospasm, coronary vasospasm),retinopathy, erectile dysfunction (ED), AIDS, osteoporosis, Crohn'sDisease and colitis, neurite outgrowth, and Raynaud's Disease. Inpreferred embodiments, the disease, condition, or disorder isatherosclerosis, hypertension, erectile dysfunction (ED),reperfusion/ischemia (e.g., stroke), or vasospasm (cerebral vasospasmand coronary vasospasm).

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a JAK, JNK, CDK, and ZAP-70 kinase.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, a psychotic disorder, an autoimmunedisorder, a condition associated with organ transplant, an inflammatorydisorder, an immunologically mediated disorder, a viral disease, or abone disorder is provided comprising administering an effective amountof a compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of a proliferative disorder, acardiac disorder, a neurodegenerative disorder, a psychotic disorder, anautoimmune disorder, a condition associated with organ transplant, aninflammatory disorder, an immunologically mediated disorder, a viraldisease, or a bone disorder. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a proliferative disorder, a cardiac disorder,a neurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorder.The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar--agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hardfilled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of protein kinases. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of JAK, JNK,CDK, and ZAP-70, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation of one or more of JAK, JNK, CDK, and ZAP-70 isimplicated in the disease, condition, or disorder. When activation ofJAK, JNK, CDK, and ZAP-70 is implicated in a particular disease,condition, or disorder, the disease, condition, or disorder may also bereferred to as “JAK, JNK, CDK, and ZAP-70-mediated disease” or diseasesymptom. Accordingly, in another aspect, the present invention providesa method for treating or lessening the severity of a disease, condition,or disorder where activation or one or more of JAK, JNK, CDK, and ZAP-70is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofJAK, JNK, CDK, and ZAP-70, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity or ATPase activity of activated JAK, JNK,CDK, and ZAP-70. Alternate in vitro assays quantitate the ability of theinhibitor to bind to JAK, JNK, CDK, and ZAP-70. Inhibitor binding may bemeasured by radiolabelling the inhibitor prior to binding, isolating theinhibitor/JAK, inhibitor/JNK, inhibitor/CDK, or inhibitor/ZAP-70 complexand determining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with JAK, INK, CDK, and ZAP-70 bound to knownradioligands.

The term “measurably inhibit”, as used herein means a measurable changein JAK, JNK, CDK, and ZAP-70 activity between a sample comprising saidcomposition and a JAK, JNK, CDK, and ZAP-70 kinase and an equivalentsample comprising JAK, JNK, CDK, and ZAP-70 kinase in the absence ofsaid composition.

The term “JAK-mediated disease”, as used herein means any disease orother deleterious condition in which a JAK family kinase is known toplay a role. Such conditions include, without limitation, immuneresponses such as allergic or type I hypersensitivity reactions, asthma,autoimmune diseases such as transplant rejection, graft versus hostdisease, rheumatoid arthritis, amyotrophic lateral sclerosis, andmultiple sclerosis, neurodegenerative disorders such as Familialamyotrophic lateral sclerosis (FALS), as well as in solid andhematologic malignancies such as leukemias and lymphomas.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a CDK2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “CDK2-mediated disease”, as used herein means any disease orother deleterious condition in which CDK2 is known to play a role.Accordingly, these compounds are useful for treating diseases orconditions that are known to be affected by the activity of CDK2 kinase.Such diseases or conditions include cancer, Alzheimer's disease,restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV,herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseasessuch as rheumatoid arthritis, viral infections, neurodegenerativedisorders, disorders associated with thymocyte apoptosis, orproliferative disorders resulting from the deregulation of the cellcycle, especially of the progression from G₁ to S phase.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a CDK2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “JNK-mediated condition”, as used herein means any disease orother deleterious condition in which JNK is known to play a role. Suchconditions include, without limitation, inflammatory diseases,autoimmune diseases, destructive bone disorders, proliferativedisorders, cancer, infectious diseases, neurodegenerative diseases,allergies, reperfusion/ischemia in stroke, heart attacks, angiogenicdisorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy,thrombin-induced platelet aggregation, and conditions associated withprostaglandin endoperoxidase synthase-2.

“JNK-mediated conditions” also include ischemia/reperfusion in stroke,heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia,cardiac hypertrophy, hepatic ischemia, liver disease, congestive heartfailure, pathologic immune responses such as that caused by T cellactivation and thrombin-induced platelet aggregation.

In addition, JNK inhibitors of the instant invention may be capable ofinhibiting the expression of inducible pro-inflammatory proteins.Therefore, other “JNK-mediated conditions” which may be treated by thecompounds of this invention include edema, analgesia, fever and pain,such as neuromuscular pain, headache, cancer pain, dental pain andarthritis pain.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a ZAP-70-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “ZAP-70-mediated condition”, as used herein means any diseaseor other deleterious condition in which ZAP-70 is known to play a role.Such conditions include, without limitation, autoimmune, inflammatory,proliferative and hyperproliferative diseases andimmunologically-mediated diseases including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS).

For example, ZAP-70-mediated conditions include diseases of therespiratory tract including, without limitation, reversible obstructiveairways diseases including asthma, such as bronchial, allergic,intrinsic, extrinsic and dust asthma, particularly chronic or inveterateasthma (e.g. late asthma airways hyper-responsiveness) and bronchitis.Additionally, ZAP-70 diseases include, without limitation, thoseconditions characterised by inflammation of the nasal mucus membrane,including acute rhinitis, allergic, atrophic thinitis and chronicrhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitispurulenta, rhinitis sicca and rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous and pseudomembranous rhinitis andscrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hayfever) and vasomotor rhinitis, sarcoidosis, farmer's lung and relateddiseases, fibroid lung and idiopathic interstitial pneumonia.

ZAP-70-mediated conditions also include diseases of the bone and jointsincluding, without limitation, (pannus formation in) rheumatoidarthritis, seronegative spondyloarthropathis (including ankylosingspondylitis, psoriatic arthritis and Reiter's disease), Behcet'sdisease, Sjogren's syndrome and systemic sclerosis.

ZAP-70-mediated conditions also include diseases and disorders of theskin, including, without limiation, psoriasis, systemic sclerosis,atopical dermatitis, contact dermatitis and other eczmatous dermitides,seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus,epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas,cutaneous eosinophilias, uveitis, Alopecia, areata and vernalconjunctivitis.

ZAP-70-mediated conditions also include diseases and disorders of thegastrointestinal tract, including, without limitation, Coeliac disease,proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis,Crohn's disease, ulcerative colitis, food-related allergies which haveeffects remote from the gut, e.g. migraine, rhinits and eczema.

ZAP-70-mediated conditions also include those diseases and disorders ofother tissues and systemic disease, including, without limiation,multiple scleroris, artherosclerosis, acquired immunodeficiency syndrome(AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto'sthyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome,eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezarysyndrome and idiopathic thrombocytopenia pupura, restenosis followingangioplasty, tumours (for example leukemia, lymphomas),artherosclerosis, and systemic lupus erythematosus.

ZAP-70-mediated conditions also include allograft rejection including,without limitation, acute and chronic allograft rejection following forexample transplantation of kidney, heart, liver, lung, bone marrow, skinand cornea; and chronic graft versus host disease.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, For example, other therapies oranticancer agents that may be used in combination with the inventiveanticancer agents of the present invention include surgery, radiotherapy(in but a few examples, gamma.-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, biologicresponse modifiers (interferons, interleukins, and tumor necrosis factor(TNF) to name a few), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g., antiemetics), and other approvedchemotherapeutic drugs, including, but not limited to, alkylating drugs(mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,Ifosfamide), antimetabolites (Methotrexate), purine antagonists andpyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec™, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http:H/www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting JAK, JNK, CDK, andZAP-70 activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of JAK, JNK, CDK, and ZAP-70 kinase activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, biological specimenstorage, and biological assays.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES

Scheme I above depicts the synthesis of several exemplary compounds. Theexamples below describe general procedures for the preparation ofcompounds herein and Table 3 depicts characterization for exemplarycompounds of the invention.

Example 1

Preparation of Guanidines

Procdure A: General Procedure for the Synthesis of Guanidines

The substituted aniline (20 mmol, 2 eq.) and cyanamide (10 mmol, 1 eq.)were taken up in Toluene (5 ml), and Triflic acid (1 ml). The reactionwas sealed and heated to 85C, overnight, with magnetic stirring. Thereaction was quenched with water (10 ml). The phases were separated andthe aqueous was made basic with 2N sodium hydroxide (10 ml). The basicaqueous phase was washed with toluene and then extracted with methylenechloride (3×) to give desired guanidine upon concentration.

Procedure B: General Procedure for the Synthesis of Guanidines

In a tube was placed cyanamide (10 mmol, 1 eq.) and substituted aniline(11 mmol, 1.1 eq). To this was added 10 ml of dioxane (alternativelyethylene glycol dimethyl ether, DME, can be used), and the mixture waswarmed to achieve dissolution. To the homogeneous solution was added 4Nhydrochloric acid in dioxane (3 ml, 12 mmol, 1.2 eq.). The tube wassealed and heated to 60C overnight with magnetic stirring. The reactionwas concentrated to dryness, basified with 2N NaOH, and extracted withmethylene chloride (2×). The organics were concentraded to give desiredguanidine.

Procedure B (Modified): General Procedure for the Synthesis ofGuanidines.

The substituted aniline (20 mmol) and cyanamide (20 mmol) were dissolvedin dioxane (25 ml) with warming. To this was added 4N hydrochloric acidin dioxane (5 ml, 20 mmol) dropwise via syringe. The reaction was heatedto reflux for three days, concentrated to dryness and dissolved inethanol. To this was added 2N sodium hydroxide (10 ml, 20 mmol)resulting in a voluminous precipitate. The solid was filtered and washedwith ether/ethanol, and then dried in-vacuo to give the desiredguanidine with 1 equivalent of sodium chloride.

Procedure D: Procedure for the Synthesis of N-methylated BenzoxazinEneaminones.

The compound 6-acetyl-2H-1,4-benzoxazin-3(4H)-one (10 mmol) was taken upin excess N,N-dimethylformamide dimethyl acetal and heated to 80C,overnight. The reaction was concentrated to dryness and used withoutpurification.

Procedure E: General Procedure for the Synthesis of N-alkylatedBenzoxazin Acetophenones.

The compound 6-acetyl-2H-1,4-benzoxazin-3(4H)-one (10 mmol) andalkylating agent (5.4 mmol, 1.1 eq.) were taken up in dimethylformamide(10 ml) with powdered potassium carbonate (36 mmol, xs). The reactionwas heated to approximately 110C for 1.5 to 24 hours. The reaction isquenched with water and extracted with ether (2×). The organics werewashed with brine, dried over sodium sulfate, filtered, and concentratedto give crude. The crude was purified via flash chromatography on silicagel, and eluted with ether or ethyl acetate).

Procedure F: General Procedure for the Synthesis of Eneaminones

The appropriate acetophenone was taken up in N,N-Dimethylformamidedimethyl acetal neat (alternatively toluene may be used as co-solvent),and heated to 95C for 1 to 3 days. Alternatively, toluene may be addedto aid dissolution. The reaction was then concentrated to an oil. Theproduct occasionally crystallized from ethyl acetate, or from ethylacetate/hexane. Otherwise, it was purified via column chromatography onsilica gel, eluted with ethyl acetate/hexane to pure ethyl acetate.

Procedure G: General Procedure for the Synthesis of Eneaminones

The appropriate acetophenone (20 mmol) was dissolved in 100 ml oftoluene (alternatively N,N-dimethylformamide or tetrahydrofuran may beused as solvent) and treated with tert-Butoxybis (dimethylamino) methane(Bredereck's reagent, 35 mmol, 1.75 eq.). The reaction was heated toreflux overnight. Upon concentration a precipitate forms, which wasfiltered, and used directly. Alternatively, the crude may be purifiedvia flash chromatography on silica gel, eluted with ethyl acetate/hexaneor acetone/hexane.

Procedure H: General Procedure for the Synthesis ofPhenylaminopyrimidines

The eneaminone (200 umol) and guanidine (300 umol to 500 umol, 1.5 to2.5 eq.) were dissolved in acetonitrile (200 uL to 500 uL). The reactionwas sealed and heated to approximately 80C, overnight. The reaction wasextracted with ethyl acetate and water. The organics were washed withbrine, dried over sodium sulfate, filtered, and concentrated to crude.The crude was either recrystallized from ethyl acetate, ethylacetate/hexane, ether, or ether/hexane. Otherwise, the crude waspurified via flash chromatography on silica gel, eluted with ethylacetate/hexane or ethyl acetate.

Procedure J: General Procedure for the Synthesis ofPhenylaminopyrimidines

The eneaminone (200 umol) and guanidine (300 umol to 500 umol, 1.5 to2.5 eq.) was dissolved in approximately 1 ml of dimethylformamide(alternatively, DMSO). The reaction was sealed and heated toapproximately 120C, overnight. The product can either be precipitatedvia addition of ethyl acetate and 1N hydrochloric acid, or purified viareverse phase HPLC using a C18 column and eluted with anacetonitrile/water (with 0.1% trifluoroacetic acid v/v) gradient.

Procedure J (modified): general procedure for the synthesis ofphenylaminopyrimidines. As per general procedure J except for theaddition of powdered potassium carbonate (1 equivalent) or excess.

TABLE 3 Table 3 below depicts the procedure sequence utilized for thepreparation of exemplary compounds. Each of the letters in the proceduresequence refers to the procedures detailed above. “X” refers to “notapplicable” and lower case letters refer to the modified procedures(also detailed above). Compound Procedures M + 1 mass m − 1 mass MWIVa-1 BXDH 333 332 IVa-2 AXDH 351 350 IVa-3 BXDH 347 346 IVa-4 BXDH 347346 IVa-5 BXDH 363 362 IVa-6 BXDH 361 360 IVa-7 BXDH 393 392 IVa-8 BXGJ319 317 318 IVa-9 AXGJ 337 335 336 IVa-10 AXGJ 337 335 336 IVa-11 BXGJ337 335 336 IVa-12 BXGJ 353 351 352 IVa-13 AXGJ 353 351 352 IVa-14 BXGJ349 347 348 IVa-15 AXGJ 333 331 332 IVa-16 XXGJ 335 334 IVa-17 BXGJ 333331 332 IVa-18 BXGJ 347 345 346 IVa-19 BXGJ 379 377 378 IVa-20 BXGJ 395393 394 IVa-21 bXGJ 398 396 397 IVa-22 BXDJ 412 410 411 IVa-23 BXGJ 398396 397 IVa-24 BXDJ 412 410 411 IVa-25 XXDJ 376 774 375 IVa-26 BXDJ 358357 IVa-27 XXDJ 349 347 348 IVa-28 BXDJ 363 362 IVa-29 BEGJ 432 431IVa-30 AEGJ 450 449 IVa-31 BEGJ 466 464 465 IVa-32 XEGJ 448 446 447IVa-33 XEGJ 490 488 489 IVa-34 XEGJ 475 473 474 IVa-35 BEGJ 524 523IVa-36 BEGJ 462 461 IVa-37 BEGJ 508 507 IVa-38 bEGJ 511 509 510 IVa-39BEGJ 511 509 510 IVa-40 BEGJ 460 459 IVa-41 BEFJ 410 409 IVa-42 AEFJ 428427 IVa-43 BEFJ 444 443 IVa-44 XEFJ 426 424 425 IVa-45 BEFJ 440 439IVa-46 XEFJ 468 467 IVa-47 XEFJ 435 433 434 IVa-48 BEFJ 486 485 IVa-49BEFJ 502 501 IVa-50 BEFJ 489 487 488 IVa-51 BEFJ 489 487 488 IVa-52 BEFJ438 437 IVa-53 XEFJ 453 452 IVa-54 BEFJ 410 409 IVa-55 AEFJ 428 427IVa-56 BEFJ 444 443 IVa-57 BEFJ 440 439 IVa-58 XEFJ 468 467 IVa-59 BEFJ486 485 IVa-60 BEFJ 502 501 IVa-61 bEFJ 489 487 488 IVa-62 BEFJ 489 487488 IVa-63 BEFJ 438 437 IVa-64 BEFJ 410 409 IVa-65 AEFJ 428 427 IVa-66BEFJ 444 443 IVa-67 XEFJ 468 467 IVa-68 BEFJ 486 485 IVa-69 BEFJ 502 501IVa-70 bEFJ 489 487 488 IVa-71 BEFJ 489 487 488 IVa-72 BEFJ 438 437

Example 16

JAK3 Inhibition Assay

Compounds were screened for their ability to inhibit JAK3 according tothe method described by G. R. Brown, et al, Bioorg. Med. Chem. Lett.2000, vol. 10, pp 575–579 in the following manner. Into Maxisorb plates,previously coated at 4° C. with Poly (Glu, Ala, Tyr) 6:3:1 then washedwith phosphate buffered saline 0.05% and Tween (PBST), was added 2 μMATP, 5 MM MgCl₂, and a solution of compound in DMSO. The reaction wasstarted with JAK enzyme and the plates incubated for 60 minutes at 30°C. The plates were then washed with PBST, 100 μL HRP-Conjugated 4G10antibody was added, and the plate incubated for 90 minutes at 30° C. Theplate was again washed with PBST, 100 μL TMB solution is added, and theplates were incubated for another 30 minutes at 30° C. Sulfuric acid(100 μL of 1M) was added to stop the reaction and the plate is read at450 nm to obtain the optical densities for analysis to determine K_(i)values.

Compounds of this invention that have K_(i)s less than 5.0 micromolar(μM) in the JAK3 inhibition assay include the following compounds:(IVa-2), (IVa-4), (IVa-5), (IVa-39), (IVa-10), (IVa-11), (IVa-13),(IVa-26), (IVa-29), (IVa-30), (IVa-31), (IVa-32), (IVa-36), (IVa-23),(IVa-24), (IVa-41), (IVa-43), (IVa-45), (IVa-46), (IVa-47), (IVa-48),(IVa-50), (IVa-52), (IVa-55), (IVa-56), (IVa-57), (IVa-58), (IVa-59),(IVa-60), (IVa-66), (IVa-70), and (IVa-72).

Compounds of this invention that have K_(i)s less than 1.0 micromolar(μM) in the JAK3 inhibition assay include the following compounds:(IVa-1), (IVa-3), (IVa-6), (IVa-7), (IVa-14), (IVa-15), (IVa-21),(IVa-22), (IVa-25), (IVa-27), (IVa-28), (IVa-44), (IVa-51), (IVa-53),(IVa-57), and (IVa-71).

Example 17

CDK2 Inhibition Assay

Compounds were screened for their ability to inhibit CDK-2/Cyclin Ausing a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7,2249). Reactions were carried out in 100 mM HEPES pH 7.5, 10 mM MgCl2,25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations inthe assay were 100 μM ATP (Sigma chemicals) and 100 μM peptide (AmericanPeptide, Sunnyvale, Calif.). Assays were carried out at 30° C. and 25 nMCDK-2/Cyclin A. Final concentrations of the components of the coupledenzyme system were 2.5 mM phosphoenolpyruvate, 350 μM NADH, 30 μg/mlpyruvate kinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of CDK-2/Cyclin A, DTT and thetest compound of interest. 56 μl of the test reaction was placed in a384 well plate followed by addition of 1 μl of 2 mM DMSO stockcontaining the test compound (final compound concentration 30 μM). Theplate was preincubated for ˜10 minutes at 30° C. and the reactioninitiated by addition of 10 μl of enzyme (final concentration 25 nM).Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compoundsshowing >50% inhibition versus standard wells containing DMSO, but nocompound, were titrated and IC₅₀'s determined using a similar protocol.

Compounds of this invention that have K_(i)s less than 1.0 micromolar(μM) in the CDK2 inhibition assay include the following compounds:(IVa-22), (IVa-23), and (IVa-24).

Example 18

JNK3 Inhibition Assays

Compounds were assayed for the inhibition of JNK3 by aspectrophotometric coupled-enzyme assay. In this assay, a fixedconcentration of activated JNK3 (10 nM) was incubated with variousconcentrations of a potential inhibitor dissolved in DMSO for 10 minutesat 30° C. in a buffer containing 0.1 M HEPES buffer, pH 7.5, containing10 mM MgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM EGF receptor peptide.The EGF receptor peptide is a phosphoryl acceptor in the JNK3-catalyzedkinase reaction. The reaction was initiated by the addition of 10 μM ATPand the assay plate is inserted into the spectrophotometer's assay platecompartment that was maintained at 30° C. The decrease of absorbance at340 nm was monitored as a function of time. The rate data as a functionof inhibitor concentration was fitted to competitive inhibition kineticmodel to determine the K_(i).

Compounds of this invention that have K_(i)s less than 1.0 micromolar(μM) in the JNK3 inhibition assay include the following compounds:(IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-22), (IVa-23), and(IVa-24).

Example 18

ZAP-70 Inhibition Assay

Compounds were screened for their ability to inhibit ZAP-70 using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl₂, 25 mM NaCl, 2 mM DTT and 3% DMSO. Final substrate concentrationsin the assay were 100 μM ATP (Sigma Chemicals) and 20 μM peptide(poly-4EY, Sigma Chemicals). Assays were carried out at 30° C. and 60 nMZAP-70. Final concentrations of the components of the coupled enzymesystem were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvatekinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ZAP-70 and the testcompound of interest. 55 μl of the stock solution was placed in a 96well plate followed by addition of 2 μl of DMSO stock containing serialdilutions of the test compound (typically starting from a finalconcentration of 15 μM). The plate was preincubated for 10 minutes at30° C. and the reaction initiated by addition of 10 μl of enzyme (finalconcentration 60 nM). Initial reaction rates were determined with aMolecular Devices SpectraMax Plus plate reader over a 15 minute timecourse. IC50 and Ki data were calculated from non-linear regressionanalysis using the Prism software package (GraphPad Prism version 3.0afor Macintosh, GraphPad Software, San Diego Calif., USA).

Compounds of this invention that have K_(i)s less than 1.0 micromolar(μM) in the ZAP-70 inhibition assay include the following compounds:(IVa-23), and (IVa-24).

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: W¹ is nitrogenor CH, W² is nitrogen or C—(J)_(p)R^(U), and W³ is nitrogen orC—(V)_(q)R^(V); p and q are each independently 0 or 1; R^(U) and R^(V)are each independently R or Ar¹; U and V are each independently a bondor a C₁₋₆ alkylidene chain, wherein up to two methylene units of thechain are optionally and independently replaced by CO, CO₂, COCO, CONR,OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR,NRSO₂NR, O, S, or NR; each occurrence of R is independently hydrogen oran optionally substituted C₁–C₄ aliphatic, or two R bound to the samenitrogen atom are optionally taken together with the nitrogen atom toform a 3–7 membered saturated, partially unsaturated, or fullyunsaturated ring having 0–2 additional heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; Ar¹ is a 5–7 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0–3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8–12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0–5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; wherein Ar¹ is optionallysubstituted with m independent occurrences of Z—R⁵; wherein m is 0–5, Zis a bond or is a C₁–C₆ alkylidene chain wherein up to two methyleneunits of Z are optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR,NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, orNR; and each occurrence of R⁵ is independently hydrogen, an optionallysubstituted aliphatic, heteroaliphatic, aryl or heteroaryl group,halogen, NO₂, CN, OR, SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, COR, CO₂R,OCOR, CON(R)₂, OCON(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, COCOR,or COCH₂COR; R¹ and R² are taken together and fused to ring B to form aheterocyclic moiety selected from one of formulae (a) through (f):

wherein each occurrence of R^(X) is independently hydrogen, QR, orQ_(n)Ar¹; n is zero or one; and Q is an optionally substituted C₁₋₄alkylidene chain, wherein one methylene unit of Q is optionally replacedby CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO,SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; R³ is hydrogen, halogen, QR,Q_(n)CN, Q_(n)NO₂, or Q_(n)Ar¹; and R⁴ is Ar¹, or T—Ar¹; wherein T is aC₁₋₂ alkylidene chain wherein one methylene wilt of T is optionallyreplaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂,NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR.
 2. The compound ofclaim 1, wherein R¹ and R² taken together form the heterocyclic moietyof formula (a) and R^(X) is hydrogen or optionally substituted C₁₋₆aliphatic.
 3. The compound of claim 1, wherein R^(X) is hydrogen,methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₆alkyl substituted with N(R)₂, or C₁₋₆alkyl substitutedwith Ar¹.
 4. The compound of claim 1, wherein R^(X) is hydrogen, methyl,or C₁₋₂alkyl substituted with a group selected from optionallysubstituted phenyl, pyridyl, morpholino, piperidinyl, or piperazinyl. 5.The compound of claim 1, wherein R³ is hydrogen, halogen, QR or QAr¹,wherein Q is a C₁₋₃ alkylidene chain wherein one methylene unit of Q isoptionally replaced by —O—, —S—, —NHCO—, or —NR—, and Ar¹ is anoptionally substituted 5–6 membered saturated, partially unsaturated, orfully unsaturated ring having 0–2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.
 6. The compound of claim 1, wherein R³is hydrogen, OH, OCH₃, OCH₂CH₃, NHCOMe, NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, O(CH₂)₂morpholin-4-yl, O(CH₂)₂NH₂, O(CH₂)₂NH(C₁₋₄aliphatic), O(CH₂)₂N(C₁₋₄ aliphatic)₂, Br, Cl, or F.
 7. The compound ofclaim 1, wherein R³ is hydrogen.
 8. The compound of claim 1, wherein R⁴is a 6-membered saturated, partially unsaturated, or aryl ring having0–3 nitrogens, a 9–10 membered bicyclic aryl ring having 0–2 nitrogenatoms, or a 5 membered heteroaryl ring having 2–3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein eachring is optionally substituted.
 9. The compound of claim 1, wherein R⁴is optionally substituted phenyl, cyclohexyl, naphthyl, pyridyl,pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl,indazolyl, or benzimidazolyl.
 10. The compound of claim 1, wherein R⁴ isan optionally substituted phenyl group.
 11. The compound of claim 8,wherein each occurrence of Z is independently a bond or a C₁₋₄alkylidene chain wherein one methylene unit of Z is optionally replacedby —O—, —S—, —SO₂—, or —NH—; and each occurrence of R⁵ is independentlyhydrogen, C₁₋₆ aliphatic, halogen, NO₂, OR, N(R)₂, or optionallysubstituted phenyl, pyridyl, or pyrimidinyl.
 12. The compound of claim8, wherein each occurrence of ZR⁵ is independently Cl, F, Br, methyl,ethyl, t-butyl, isopropyl, cyclopropyl, nitro, CN, OMe, OEt, CF₃, NH₂,phenyl, benzyl, benzyloxy, OH, methylenedioxy, SO₂NH₂, CONH₂, CO₂Me,phenoxy, O-pyridinyl, SO₂phenyl, nitrophenoxy, aminophenoxy,S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl, phenol,chloro-fluoro-phenyl, dimethylaminophenyl, CF₃-phenyl, dimethylphenyl,chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy,ethoxyphenoxy, and fluorophenoxy.
 13. The compound of claim 1, wherein(U)_(p)R^(U) and (V)_(q)R^(V) are each independently hydrogen, halogen,NO₂, CN, OR, SR or N(R)₂, or C₁₋₄ aliphatic optionally substituted withoxo, OR, SR, N(R)₂, halogen, NO₂ or CN.
 14. The compound of claim 1,wherein (U)_(p)R^(U) and (V)_(q)R^(V) are each independently hydrogen,Me, OH, or OMe.
 15. The compound of claim 1, wherein W¹ is N or CH andcompounds have the structure of Formula Ia or Ib:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15 wherein R⁴ an optionally substituted phenyl group and compounds havethe structure of Formula IIa or IIb:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim16 wherein R³ is hydrogen, and compounds have the structure of FormulaIIIa or IIIb:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim16, wherein R³ hydrogen, and R¹ and R² taken together form theheterocyclic moiety of formula (a) and compounds have the structure ofFormula IVa or IVb:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim15, wherein i) R¹ and R² taken together form the heterocyclic moiety offormula (a); where R^(X) is defined according to one of the followinggroups: (a) hydrogen or optionally substituted C₁₋₆aliphatic; (b)hydrogen, methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₆alkyl substituted with N(R)₂, orC₁₋₆alkyl substituted with Ar¹; or (c) hydrogen, methyl, or C₁₋₂alkylsubstituted with a group selected from optionally substituted phenyl,pyridyl, morpholino, piperidinyl, or piperazinyl; ii) R³ is definedaccording to one of the following groups: (a) hydrogen, halogen, QR orQAr¹, wherein Q is a C₁₋₃ alkylidene chain wherein one methylene unit ofQ is optionally replaced by —O—, —S—, —NHCO—, or —NR—, and Ar¹ is anoptionally substituted 5–6 membered saturated, partially unsaturated, orfully unsaturated ring having 0–2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; (b) hydrogen, OH, OCH₃, OCH₂CH₃,NHCOMe, NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,O(CH₂)₂morpholin-4-yl, O(CH₂)₂NH₂, O(CH₂)₂NH(C₁₋₄ aliphatic),O(CH₂)₂N(C₁₋₄ aliphatic)₂, bromo, chloro, or fluoro; or (c) hydrogen;iii) R⁴ is defined according to one of the following groups: (a) a6-membered saturated, partially unsaturated, or aryl ring having 0–3nitrogens, a 9–10 membered bicyclic aryl ring having 0–2 nitrogens, or a5 membered heteroaryl ring having 2–3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein said ring is optionallysubstituted with (ZR⁵)_(m); (b) an optionally substituted ring selectedfrom phenyl, cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl, orbenzimidazolyl, wherein said ring is optionally substituted with(ZR⁵)_(m); or (c) an optionally substituted phenyl group, wherein saidphenyl group is optionally substituted with (ZR⁵)_(m); iv) W¹, W² and W³are defined according to one of the following groups: (a) W¹ is nitrogenor CH, W² is nitrogen or C—(U)_(p)R^(U), and W³ is nitrogen orC—(V)_(q)R^(V); (b) W¹ is nitrogen or CH, W² is C—(U)_(p)R^(U), and W³is C—(V)_(q)R^(V); or (c) W¹ is nitrogen or CH and W² and W³ are eachCH; and v) (U)_(p)R^(U) and (V)_(q)R^(V) groups are defined according toone of the following groups: (a) hydrogen, halogen, NO₂, CN, OR, SR orN(R)₂, or C₁₋₄aliphatic optionally substituted with oxo, OR, SR, N(R)₂,halogen, NO₂ or CN; (b) hydrogen, Me, OH, OMe or N(R)₂; or (c) both(U)_(p)R^(U) and (V)_(q)R^(V) are hydrogen.
 20. The compound of any oneof claims 16, 17, 18 or 19, wherein each occurrence of Z isindependently a bond or a C₁₋₄ alkylidene chain wherein one methyleneunit of Z is optionally replaced by —O—, —S—, —SO₂—, or —NH—; and eachoccurrence of R⁵ is independently hydrogen, C₁₋₆ aliphatic, halogen,NO₂, OR, N(R)₂, or optionally substituted phenyl, pyridyl, andpyrimidinyl.
 21. The compound of claim 20, wherein each occurrence ofZR⁵ is independently Cl, F, Br, methyl, ethyl, t-butyl, isopropyl,cyclopropyl, nitro, CN, OMe, OEt, CF₃, NH₂, phenyl, benzyl, benzyloxy,OH, methylenedioxy, SO₂NH₂, CONH₂, CO₂Me, phenoxy, O-pyridinyl,SO₂phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NHphenyl,NH-methoxyphenyl, pyridinyl, phenol, chloro-fluoro-phenyl,dimethylaminophenyl, CF₃-phenyl, dimethylphenyl, chlorophenyl,fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, orfluorophenoxy.
 22. The compound of claim 18 having the formula IVa,wherein R^(X) is hydrogen or optionally substituted C₁₋₆aliphatic; m is0, 1 or 2; and ZR⁵ is Cl, F, Br, methyl, ethyl, t-butyl, isopropyl,cyclopropyl, nitro, CN, OMe, OEt, CF₃, NH₂, phenyl, benzyl, benzyloxy,OH, methylenedioxy, SO₂NH₂, CONH₂, CO₂Me, phenoxy, O-pyridinyl,SO₂phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrunidine, NHphenyl,NH-methoxyphenyl, pyridinyl, phenol, chloro-fluoro-phenyl,dimethylaminophenyl, CF₃-phenyl, dimethylphenyl, chlorophenyl,fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, orfluorophenoxy.
 23. The compound of claim 1, selected from one of thefollowing compounds:


24. A pharmaceutical composition comprising a compound according toclaim 1, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 25. A method of treating or lessening the severity of a diseaseor disorder selected from an allergic or type I hypersensitivityreaction, asthma, transplant rejection, graft versus host disease, orrheumatoid arthritis, comprising administering to a subject in needthereof a compound of claim 1 or a composition comprising said compound.26. The method of claim 25, comprising the further step of administeringto said patient an additional therapeutic agent selected from atreatment for asthma, an anti-inflammatory agent, or an immunomodulatoryor immunosuppressive agent, wherein: said additional therapeutic agentis appropriate for the disease being treated; and said additionaltherapeutic agent is administered together with said composition as asingle dosage form or separately from said composition as part of amultiple dosage form.